Reconstructing mouse embryogenesis through self-organizing ES-cell based models

Alexandre Mayran, PhD
Scientist
Swiss Institute for Experimental Cancer Research (ISREC)
Swiss Federal Institute of Technology (EPFL)
Lausanne, Switzerland

Lieu : 
Auditorium de l'IRCM
Accès par le 110, avenue des Pins O, H2W 1R7 Montréal

About this conference

Recent years have seen the emergence of a diversity of 3D in vitro models which can mimic various steps of mammalian embryogenesis. In this presentation I will be discussing how the field of synthetic embryogenesis is quickly advancing and how these can be a useful tool, not only to replace animal experimentation but to provide tools to scale up the discovery process.
 
Namely our research focuses on one model of post-implantation embryos, called gastruloids. These are derived from mouse embryonic stem cells (ESC) which can be stimulated to undergo gastrulation-like events. These 3D structures can mimic post-implantation embryos and provide a useful tool to investigate early embryogenesis which is typically limited by the implantation into the uterine wall. Gastruloids undergo cell fate diversification, break symmetry, and self-organize along a single antero-posterior axis without external polarizing cues.

The main part of the presentation will focus on understanding the molecular underlying of gastruloid self-organization and its interplay with cell fate specification. Natural embryos rely on signals coming from the extra-embryonic tissue which gastruloids lack, thus we asked how do these structures manage to reach an embryo-like organization.

First, we found that gastruloid self-organization is associated to an epithelial to mesenchymal transition (EMT) with a switch from E- to N-Cadherin. Using a combination of single cell transcriptomic, and imaging of gastruloids with high temporal resolution, we found that the timing of EMT completion, but not its initiation, is differentially regulated among cell types within the gastruloid. Then, by generating a series of genetically modified ESC lines, we dissected the EMT process and its function during gastruloid’s development. Interestingly, we found that not all EMT steps are required for self-organization, interfering with N-Cadherin had no impact on self-organization. However, E-Cadherin repression is crucial for proper gastruloid organization, and in its absence gastruloids frequently elongate along multiple axes. Finally, this also has a strong impact on gastruloid cell differentiation.  Both cell fate proportions and differentiation pace of the two major gastruloid lineages (Ectoderm and mesoderm) is severely affected.
In summary, we propose that an interplay between cell fate acquisition and EMT is critical for gastruloid self-organization.
 

About Alexandre Mayran
Alexandre Mayran grew up in Strasbourg, France, and moved to Montreal for his graduate studies here at the IRCM. He obtained his PhD in 2019 from the laboratory of Prof. Jacques Drouin, where he was studying the chromatin remodeling activity of pioneer transcription factors during cell specification of the pituitary. Then, he performed his post-doctoral training under a Human Frontier Science Program Fellowship, where he was hosted by the laboratory of Prof. Denis Duboule at the École Polytechnique Fédérale de Lausanne. There, he aimed at understanding how in vitro models of embryogenesis are able to self-organize in a manner that resemble natural embryos. He recently secured funding to investigate how we can improve these in vitro models to better mimic natural embryos and to develop molecular tools and methods to study developmental processes such as patterning and gene regulation using pseudo-embryos.

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